The long-term objective of this program is to provide new, useful information on mechanisms by which gastrointestinal hormones (GIH) and related compounds influence body function. We plan to study the synthesis, storage, release, transport,a nd mechanisms of action of these agents on target cells, target-cell responses, the hormone-hormone interrelationships of these peptides, and their gene expression. In Project 1, we will examine the mechanisms underlying age-related changes in GI hormone metabolism and in responses of the gut and pancreas to trophic stimuli. We will determine the mechanisms by in which age-related changes in GI function may relate to development of disease. In Project 2, we will examine the relevance of chromogranin and its physiologic role in the GI tract and pancreas. We will investigate the action of pancreastatin on the release of insulin from the pancreas. In Project 3, we will examine the effects of GIH hormones on growth of cancers. We will study the mechanisms of trophic actions of GIH. We will determine the role of growth factors in control of growth of GI pancreatic cancers. In Project 4, we will explore expression of mRNA for parathyroid hormone-related protein and calcitonin gene-related peptide by gut tissues and cells. We will determine the location of the peptides in the gut, identify cellular sites of synthesis and examine the regulation of mRNA expression by the cells. In Project 5, we will define cellular and intracellular mechanisms that mediate effects of steroids on functions of gut and pancreas and on the growth of colonic and pancreatic cancer cells. We will characterize estradiol-binding proteins from various gut and pancreatic tissues. In Project 6, we will define the intracellular mechanisms that mediate secretory and growth effects of bombesin/GRP-related peptides on gut and pancreatic tissues. In Project 7, we will study circadian and seasonal fluctuations of GI peptides with regard to physiologic and pathologic states of GI functions in animals. We have established a new Molecular Pathobiology Core to study the effects of trophic gut peptides on expression of cell cycle-related genes and on the expression of autocrine growth factors. Histological localization of neuropeptide gene expression and regulatory mechanisms that affect the level of expression will be examined. Since the last competitive review, we have demonstrated by our publications that our collaboration has been productive; many publications relate to more than one project. With the support of this grant, we have continued to further expand the depth and breadth of our research to meet the long-term objective of this program.